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Actiq Q&A

ADVERSE REACTIONS

PRE-MARKETING CLINICAL TRIAL EXPERIENCE

The safety of Actiq has been evaluated in 257 opioid tolerant chronic cancer pain patients. The duration of Actiq use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days.

The adverse events seen with Actiq are typical opioid side effects. Frequently, these adverse events will cease or decrease in intensity with continued use of Actiq, as the patient is titrated to the proper dose. Opioid side effects should be expected and managed accordingly.

The most serious adverse effects associated with all opioids are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. All patients should be followed for symptoms of respiratory depression.

Because the clinical trials of Actiq were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received Actiq for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of Actiq therapy, or cancer-related symptoms. Adverse events are included regardless of causality or severity.

Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. The goal of titration in these trials was to find the dose of Actiq that provided adequate analgesia with acceptable side effects (successful dose). Patients were titrated from a low dose to a successful dose in a manner similar to current titration dosing guidelines. Table 3 lists by dose groups, adverse events with an overall frequency of 1% or greater that occurred during titration and are commonly associated with opioid administration or are of particular clinical interest. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Adverse events are listed in descending order of frequency within each body system.

Table 3.
Percent of Patients with Specific Adverse Events Commonly
Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients)

Dose Group

200-600 mcg

800-1400 mcg

1600 mcg

>1600 mcg

Any

Number of Patients

230

138

54

41

254

Body As A Whole

Asthenia

6

4

0

7

9

Headache

3

4

6

5

6

Accidental Injury

1

1

4

0

2

Digestive

Nausea

14

15

11

22

23

Vomiting

7

6

6

15

12

Constipation

1

4

2

0

4

Nervous

Dizziness

10

16

6

15

17

Somnolence

9

9

11

20

17

Confusion

1

6

2

0

4

Anxiety

3

0

2

0

3

Abnormal Gait

0

1

4

0

2

Dry Mouth

1

1

2

0

2

Nervousness

1

1

0

0

2

Vasodilatation

2

0

2

0

2

Hallucinations

0

1

2

2

1

Insomnia

0

1

2

0

1

Thinking Abnormal

0

1

2

0

1

Vertigo

1

0

0

0

1

Respiratory

Dyspnea

2

3

6

5

4

Skin

Pruritus

1

0

0

5

2

Rash

1

1

0

2

2

Sweating

1

1

2

2

2

Special Senses

Abnormal Vision

1

0

2

0

2

The following adverse events not reflected in Table 3 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.

A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 4 lists by dose groups, adverse events with an overall frequency of 1% or greater that occurred during the long-term extension study and are commonly associated with opioid administration or are of particular clinical interest. Adverse events are listed in descending order of frequency within each body system.

Table 4.
Percent of Patients with Adverse Events Commonly Associated with
Opioid Administration or of Particular Clinical Interest Which Occurred During Long-Term Treatment (Events in 1% or More of Patients)

Dose Group

200-600 mcg

800-1400 mcg

1600 mcg

>1600 mcg

Any

Number of Patients

98

83

53

27

152

Body As A Whole

Asthenia

25

30

17

15

38

Headache

12

17

13

4

20

Accidental Injury

4

6

4

7

9

Hypertonia

2

2

2

0

3

Digestive

Nausea

31

36

25

26

45

Vomiting

21

28

15

7

31

Constipation

14

11

13

4

20

Intestinal Obstruction

0

2

4

0

3

Cardiovascular

Hypertension

1

1

0

0

1

Nervous

Dizziness

12

10

9

0

16

Anxiety

9

8

8

7

15

Somnolence

8

13

8

7

15

Confusion

2

5

13

7

10

Depression

9

4

2

7

9

Insomnia

5

1

8

4

7

Abnormal Gait

5

1

0

0

4

Dry Mouth

3

1

2

4

4

Nervousness

2

2

0

4

3

Stupor

4

1

0

0

3

Vasodilatation

1

1

4

0

3

Thinking Abnormal

2

1

0

0

2

Abnormal Dreams

1

1

0

0

1

Convulsion

0

1

2

0

1

Myoclonus

0

0

4

0

1

Tremor

0

1

2

0

1

Vertigo

0

0

4

0

1

Respiratory

Dyspnea

15

16

8

7

22

Skin

Rash

3

5

8

4

8

Sweating

3

2

2

0

4

Pruritus

2

0

2

0

2

Special Senses

Abnormal Vision

2

2

0

0

3

Urogenital

Urinary Retention

1

2

0

0

2

The following events not reflected in Table 4 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.

POST-MARKETING EXPERIENCE

The following adverse reactions have been identified during postapproval use of Actiq. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to Actiq.

DRUG ABUSE AND DEPENDENCE

Fentanyl is a mu-opioid agonist and a Schedule II controlled substance that can produce drug dependence of the morphine type. Actiq may be subject to misuse, abuse and addiction.

The administration of Actiq should be guided by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with chronic cancer pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain.

Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.

The handling of Actiq should be managed to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law (see SAFETY AND HANDLING).

REPORTS OF SUSPECTED ACTIQ SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Actiq. The information is not vetted and should not be considered as verified clinical evidence.